Mitochondrial monoamine oxidase (MAO) is the key enzyme in the pathway for metabolism of neurotransmitter amines in the central nervous system. It, thus, plays an important role in behavior and information processing in the brain and has been implicated in a number of mental disorders. The enzyme exists as a series of multiple forms specific for different types of neurotransmitter. In spite of over a decade of intensive research little is known about the structural basis of these multiple forms, i.e., whether they are separate gene products. or the result of posttranslational modifications, different membrane environments or environmental regulatory effects. A second important area of controversy is whether MAO levels in blood platelets can be used as a marker in clinical diagnosis of schizophrenia and other mental disorders in which malfunction of brain MAO is implicated. This research is intended to offer new approaches to both these important biochemical and clinical problems. With respect to the structural basis of the multiple forms, one approach we intend to use involves complementary examination of effects of environmental perturbations on aspects on catalysis and active site conformation using spectroscopic probes (spin labels) to help define which of these are important in determining and regulating substrate specificity. Most important of the effects to be considered is the lipid environment of this membrane bound enzyme. We also intend to prepare monoclonal antibodies to the individual multiple forms for use in distinguishing and characterizing elements of peptide structure unique to each to respond to the question of whether they are separate gene products. These will also be useful in purifying and separating MAO's as histochemical stains and as a clinical diagnostic tool. With respect to evaluation of the role of blood platelet MAO in schizophrenia we will use new methodologies for isolating and quantitating MAO (including those form our biochemical studies) and these will be applied to a new, large scale clinical study in which we are collaborators.